The purpose of this Clinical Investigator Development Award is to prepare the candidate, Dr. Julio C. Delgado, MD, for a career as an independent investigator in infectious diseases with a special emphasis on the genetic and immunological mechanisms associated with susceptibility to tuberculosis infection. The applicant proposes a 5-year training and research program that will prospectively identify novel host factors that predispose individuals to develop pulmonary tuberculosis in a population from Cambodia and characterize the events associated with the anergic state induced by tuberculosis infection in the intact human host. In Specific Aim 1, he will test the hypothesis that HLA molecules are functionally associated with tuberculosis progression and differential immune response to PPD and whether polymorphisms of the promoter region of certain cytokines are associated with impaired immune response against tuberculosis infection. In Specific Aim 2 and 3, he will characterize immunological and chromatin structural mechanisms associated with anergy to PPD in a cohort of tuberculosis patients from Cambodia with persistent and specific lack of response to PPD. Tuberculosis infection and pathogenesis are the result of a balance between the virulence of a particular invading organism and the host immune response. Susceptibility to tuberculosis in human populations is likely to be due to a complex interaction between several genetic, immunological and environmental factors. The experiments proposed in this application would attempt to identify host genetic factors and unveil abnormal immunological mechanisms leading to increase risk of clinical tuberculosis disease. It is anticipated that these results will be useful in the development of genetic and immune therapeutic strategies to combat tuberculosis.